The objective of the proposed research is the development of an understanding of the role of maternal and embryonic teratogen metabolism and its application to the development of a simple, reliable teratologic screening test. This research combines whole embryo culture with current pharmacological methods. Species, strains and individuals are known to possess different genetically programmed and environmentally modified bitransformational pathways. We hypothesize that their individual teratogenic responses to drugs and chemicals are shaped by these quantitative and qualitative metabolic differences. Embryos are known to have negligible biotransformational abilities. We might therefore expect a rat embryo to develop the defects characteristic of another species if presented with the teratogenic metabolites generated by that other species. In our test system, early somite rat embryos are cultured in media containing a teratogen, hepatic enzyme systems (S-9) and cofactors for a specific metabolic process. S-9 can be prepared from a number of animal sources, including humans. Cultures are incubated for 24 to 48 hours during which time control growth and development approximate normal limits. Analysis includes morphology, histology and protein content. Using this system, we have demonstrated that cyclophosphamide and procarbazine require biotransformation in order to exert teratologic effects and that Cytochalasin D undergoes bioinactivation via P-450-dependent monooxygenation. Inhibitors of these processes, including CO and metyrapone inhibit bioactivation or inactivation of these teratogens. By substitution of various cofactors, including agents and inhibitors, as well as by the use of different hepatic microsome sources, we hope to gain further information about teratogenic activation in different animals.